A reference human induced pluripotent stem cell line for large-scale collaborative studies

Cell stem cell, Journal Year: 2022, Volume and Issue: 29(12), P. 1685 - 1702.e22

Published: Dec. 1, 2022

Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between makes it challenging to replicate key findings integrate data across research groups. To address this issue, we sub-cloned candidate human iPSC deeply characterized their genetic properties using whole genome sequencing, genomic stability upon CRISPR-Cas9-based gene editing, including differentiation commonly used types. These studies identified KOLF2.1J as an all-around well-performing line. We then shared with groups around world who tested its performance in head-to-head comparisons own preferred diverse range of protocols functional assays. On strength these findings, have made gene-edited derivative clones readily accessible promote standardization required large-scale collaborative science field.

Language: Английский

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A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models

Nature Neuroscience, Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 12, 2023

Abstract Loss-of-function variants of TREM2 are associated with increased risk Alzheimer’s disease (AD), suggesting that activation this innate immune receptor may be a useful therapeutic strategy. Here we describe high-affinity human TREM2-activating antibody engineered monovalent transferrin (TfR) binding site, termed transport vehicle (ATV), to facilitate blood–brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared standard anti-TREM2 antibody. In induced pluripotent stem cell (iPSC)-derived microglia, proliferation mitochondrial metabolism. Single-cell RNA sequencing morphometry revealed shifted microglia metabolically responsive states, which were distinct from those by amyloid pathology. an AD mouse model, boosted microglial activity glucose Thus, represents promising approach improve function treat hypometabolism found patients AD.

Language: Английский

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Connecting aging biology and inflammation in the omics era

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(14)

Published: July 14, 2022

Aging is characterized by the accumulation of damage to macromolecules and cell architecture that triggers a proinflammatory state in blood solid tissues, termed inflammaging. Inflammaging has been implicated pathogenesis many age-associated chronic diseases as well loss physical cognitive function. The search for mechanisms underlie inflammaging focused initially on hallmarks aging, but it rapidly expanding multiple directions. Here, we discuss threads connecting cellular senescence mitochondrial dysfunction impaired mitophagy DNA damage, which may act hub We explore emerging multi-omics efforts aspire define complexity - identify molecular signatures novel targets interventions aimed at counteracting excessive inflammation its deleterious consequences while preserving physiological immune response. Finally, review evidence involved brain aging neurodegenerative diseases. Our goal broaden research agenda with an eye new therapeutic opportunities.

Language: Английский

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TREM2 dependent and independent functions of microglia in Alzheimer’s disease

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: Dec. 23, 2022

Abstract Microglia are central players in brain innate immunity and have been the subject of extensive research Alzheimer’s disease (AD). In this review, we aim to summarize genetic functional discoveries that advanced our understanding microglia reactivity AD pathology. Given heightened risk posed by rare variants microglial triggering receptor expressed on myeloid cells 2 (TREM2), will focus studies addressing impact responses amyloid plaques, tauopathy demyelination pathologies mouse human. Finally, discuss implications recent TREM2 biology potential therapeutic strategies for AD.

Language: Английский

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Distinct molecular profiles of skull bone marrow in health and neurological disorders

Cell, Journal Year: 2023, Volume and Issue: 186(17), P. 3706 - 3725.e29

Published: Aug. 1, 2023

The bone marrow in the skull is important for shaping immune responses brain and meninges, but its molecular makeup among bones relevance human diseases remain unclear. Here, we show that mouse has most distinct transcriptomic profile compared with other states of health injury, characterized by a late-stage neutrophil phenotype. In humans, proteome analysis reveals distinct, differentially expressed neutrophil-related pathways unique synaptic protein signature. 3D imaging demonstrates structural cellular details skull-meninges connections (SMCs) veins. Last, using translocator positron emission tomography (TSPO-PET) imaging, reflects inflammatory disease-specific spatial distribution patients various neurological disorders. anatomical functional potential as site diagnosing, monitoring, treating diseases.

Language: Английский

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Single-cell transcriptomic atlas-guided development of CAR-T cells for the treatment of acute myeloid leukemia

Nature Biotechnology, Journal Year: 2023, Volume and Issue: 41(11), P. 1618 - 1632

Published: March 13, 2023

Language: Английский

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Lysosomal acidification dysfunction in microglia: an emerging pathogenic mechanism of neuroinflammation and neurodegeneration

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: Aug. 5, 2023

Microglia are the resident innate immune cells in brain with a major role orchestrating responses. They also provide frontline of host defense central nervous system (CNS) through their active phagocytic capability. Being professional phagocyte, microglia participate and autophagic clearance cellular waste debris as well toxic protein aggregates, which relies on optimal lysosomal acidification function. Defective microglial leads to impaired functions result perpetuation neuroinflammation progression neurodegeneration. Reacidification lysosomes has been shown reverse neurodegenerative pathology Alzheimer's disease. In this review, we summarize key factors mechanisms contributing impairment associated dysfunction microglia, how these defects contribute We further discuss techniques monitor pH therapeutic agents that can reacidify under disease conditions. Finally, propose future directions investigate lysosome-mitochondria crosstalk neuron-glia interaction for more comprehensive understanding its broader CNS physiological pathological implications.

Language: Английский

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TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4

Neuron, Journal Year: 2022, Volume and Issue: 111(2), P. 202 - 219.e7

Published: Nov. 10, 2022

Language: Английский

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Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency

The EMBO Journal, Journal Year: 2022, Volume and Issue: 41(4)

Published: Jan. 12, 2022

Haploinsufficiency of the progranulin (PGRN)‐encoding gene (GRN) causes frontotemporal lobar degeneration (GRN‐FTLD) and results in microglial hyperactivation, TREM2 activation, lysosomal dysfunction, TDP‐43 deposition. To understand contribution hyperactivation to pathology, we used genetic pharmacological approaches suppress TREM2‐dependent transition microglia from a homeostatic disease‐associated state. Trem2 deficiency Grn KO mice reduced hyperactivation. explore antibody‐mediated modulation states, identified antagonistic antibodies. Treatment macrophages GRN‐FTLD patients with these antibodies led signaling due its enhanced shedding. Furthermore, antibody‐treated PGRN‐deficient derived human‐induced pluripotent stem cells showed signaling, phagocytic activity, but dysfunction was not rescued. Similarly, lipid dysregulation, glucose hypometabolism were rescued by ablation. Synaptic loss neurofilament light‐chain (NfL) levels, biomarker for neurodegeneration, further elevated Grn/Trem2 cerebrospinal fluid (CSF). These findings suggest that models GRN does promote neurotoxicity, rather neuroprotection.

Language: Английский

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Microglial efferocytosis: Diving into the Alzheimer’s disease gene pool

Neuron, Journal Year: 2022, Volume and Issue: 110(21), P. 3513 - 3533

Published: Nov. 1, 2022

Genome-wide association studies and functional genomics have linked specific cell types, genes, pathways to Alzheimer's disease (AD) risk. In particular, AD risk alleles primarily affect the abundance or structure, thus activity, of genes expressed in macrophages, strongly implicating microglia (the brain-resident macrophages) etiology AD. These converge on (endocytosis/phagocytosis, cholesterol metabolism, immune response) with critical roles core macrophage functions such as efferocytosis. Here, we review these pathways, highlighting relevant identified latest genetics studies, describe how they may contribute pathogenesis. Investigating impact AD-associated variants is essential for elucidating mechanisms developing effective therapeutic approaches.

Language: Английский

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